Along with the arrival of an aging society, the medical treatment of senile diseases has been drawing much attention. Above all, senile dementia has become a serious social problem, and various developments have been made in an attempt to provide new pharmaceuticals to cope with the problem. The conventional agents for the treatment of amnesia and dementia have been named obscurely as cerebral circulation improving agents, cerebral metabolism activator or cerebral function improving agents according to their action mechanisms. While they are effective for improving peripheral symptoms such as depression, emotional disturbances, abnormal behavior, etc., they do not show definite effects on the central symptoms of dementia, such as memory disorder, disorientation, and the like. Thus, the development of medicaments which can offer dependable action and effect on these symptoms is earnestly desired.
In the meantime, prolyl endopeptidase; EC, 3.4.21.26 is an enzyme known to act on peptides containing proline and to specifically cleave out the carboxyl side of proline. Further, this enzyme is known to act on neurotransmitters such as thyrotropin-releasing hormone (TRH), substance P and neurotensin, as well as on vasopressin which is presumably concerned with learning and memory process, to cause decomposition and inactivation of them.
In view of the foregoing findings, a compound possessing inhibitory activity on prolyl endopeptidase is expected to suppress decomposition and inactivation of vasopressin, etc., thereby suggesting its potential application to the treatment and prevention of amnesia and dementia as an efficacious medicament which exhibits direct action on the central symptoms of dementia [See Seikagaku, 55, 831 (1983); FOLIA PHARMACOL. JAPON, 89, 243 (1987); and J. Pharmacobio-Dyn., 10, 730 (1987)] and also, such compound is expected to suppress decomposition and inactivation of hormones and neurotransmitters such as TRH, substance P, neurotensin, etc., thereby improving various symptoms caused by the decomposition and inactivation of these substances.
In recent years, it has been found that beta amyloid protein shows neurotoxic action in in vitro and in vivo experiments, and that it plays essentially an important role in the onset of Alzheimer's disease. In view of the hypothesis that prolyl endopeptidase is an enzyme which cleaves out beta amyloid from amyloid precursor protein (FEBS Lett., 260, 131-134 (1990), and experiment results substantiating that substance P can suppress neurotoxic action of beta amyloid protein (Proc. Natl. Acad. Sci. USA, 88, 7247-7251 (1991), prolyl endopeptidase inhibitor is speculated to make an effective drug for treating Alzheimer's disease.
Out of the motivation described above, there has been attempted development of prolyl endopeptidase-inhibiting agents, and various proline derivatives are described and disclosed in, for example, Japanese Patent Unexamined Publication Nos. 188317/1985, 148467/1987, 42475/1989, 6263/1989, 230578/1989, and 28149/1990.